Tyrosine kinase is an enzyme which phosphorylates tyrosine residues in substrate proteins, and is known to play an important role in an intracellular signal transduction system concerning cellular differentiation and proliferation. Especially, it is known that a growth factor receptor tyrosine kinase (hereinafter receptor tyrosine kinase) such as HER2 (also called as ErbB2 or Neu) and EGF receptor etc. are considerably involved in cancer development, and their activities are increased in a variety of human cancers (Non-Patent Literature 1, Non-Patent Literature 2 and Non-Patent Literature 3).
Also it is known that co-expression of EGF receptor and HER2 further promotes canceration by EGF receptor alone (Non-Patent Literature 4) and a dual inhibitor that inhibits tyrosine kinase of both EGF receptor and HER2 is advantageous in having superior therapeutic effect in wider range of disease by synergistic effect of dual inhibition when compared with a EGF receptor or a HER2 selective inhibitor.
A quinazoline derivative (VI) having a substituent containing an alkoxyimino structure at 6-position:
wherein R2 is a hydrogen atom, halogen, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or formula: —Y—Ry wherein Y is —O—, —S—, —SO2— or alkylene which may be intervened with —O—, —S— or —N(Rz)—; and Ry is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; Rz is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl or substituted or unsubstituted aralkyloxycarbonyl;R3 and R4 are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, halogen, hydroxy, mercapto, cyano or substituted or unsubstituted amino; R5 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl or substituted or unsubstituted amino, and R6 is substituted or unsubstituted C1-3 alkylene, is one of these dual inhibitors and is expected as a novel cancer agent (Patent Literature 1).
A compound (III) having a 1-oxo-2-butyn-1-yl substituent at 6-position:
wherein R2, R3 and R4 are as defined above,is an important synthetic intermediate for preparing a quinazoline derivative (VI), since the above quinazoline derivative (VI) is prepared by reacting a compound (III) with an alkoxyamine derivative.